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A review on advanced atrioventricular block in young or middle-aged adults

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A review on advanced atrioventricular block in young or middle-aged adults
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  REVIEW A Review on Advanced Atrioventricular Block in Youngor Middle-Aged Adults S´ ERGIO NUNO CRAVEIRO BARRA, M.D., RUI PROVIDˆENCIA, M.D., M.Sc., LU´ IS PAIVA,M.D., M.Sc., JOS´ E NASCIMENTO, M.D., and ANT ´ ONIO LEIT ˜ AO MARQUES, M.D. From the Cardiology Department, Coimbra Hospital and University Centre, Centro Hospitalar de Coimbra, Coimbra,Portugal Complete atrioventricular block is a relatively uncommon arrhythmia that is nonetheless increasingly seen in elderly people of developed countries, due to the increase in life expectancy. Congenital and degenerativeetiologiesarethemostcommonlyseenamongyoungandoldpatients,respectively.However,scientific literature is surprisingly scarce regarding the etiology of complete atrioventricular block inthe asymptomatic otherwise healthy young and middle-aged adult population. Coronary artery disease,autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis, history of acuteor chronic infectious or hypersensitivity myocarditis, infiltrative processes, hypothyroidism, congenital cardiopathies such as left ventricular noncompaction or Ebstein anomaly, lamin A/C mutations,and pathologic hypervagotony and idiopathic degenerative scleroatrophy of the atrioventricular  junctional specialized tissue (Lenegre-Lev disease) are among the most frequent etiologies of completeatrioventricular block in young or middle-aged adults. To our knowledge, no comprehensive review onthe specificities of the investigation warranted in this age group has ever been developed, nor have theimplications of particular diagnoses on treatment modalities been appropriately addressed. We aim at reviewingthemostfrequentdifferentialdiagnoses ofadvanced atrioventricularblockinotherwisehealthy asymptomatic or mildly symptomatic young or middle-aged adults and their impact on therapeutic options. Additionally, we suggest a diagnostic algorithm that may be helpful in this group of patients.(PACE 2012; 00:1–11) complete atrioventricular block  ,  atrioventricular block etiology  ,  cardiac conduction Introduction Completeheartblock,alsoreferredtoasthird-degree heart block or third-degree atrioventricular(AV) block, is a disorder of the cardiac conductionsystem where there is complete dissociation of theatrial and ventricular activity due to the absenceof conduction through the atrioventricular node(AVN) or His-Purkinje system. Although MobitzI second-degree AV block is observed in 1–2% of healthy young people, especially during sleep, theprevalenceofthird-degreeAVblockisonly0.02%in the United States and 0.04% worldwide. 1 , 2 Itsincidenceincreaseswithadvancingage(highestinpeople older than 70 years), despite an early peakin infancy and early childhood due to congenital Conflicts of interest: None.Financial support: None.Address for reprints: S´ ergio Nuno Craveiro Barra, M.D., R.Ant´ onio F. Fiandor 112 – 4 Dto, 4430–017 V. N. Gaia, Portugal.E-mail: sergioncbarra@gmail.comReceived March 27, 2012; revised May 12, 2012; accepted June11, 2012.doi: 10.1111/j.1540-8159.2012.03489.x complete AV block. This latter form of heart block occurs in one out of each 20–22,000 births,usually associates with maternal antibodies to Ro(SS-A) and La (SS-B) and maternal lupus, andshows a 60% female preponderance (against a60% male preponderance for acquired completeheart block). 3 Acquired AV block results from variouspathologic states causing infiltration, fibrosis, orloss of connection in portions of the healthyconduction system. The underlying conditionstrongly influences both the age of presenta-tion/onset and the prognosis. To the best of our knowledge, no comprehensive review on thespecificities of the investigation warranted in oth-erwise healthy young or middle-aged adults withcomplete asymptomatic or mildly symptomaticAV block has ever been developed, nor have theimplications of particular diagnoses on treatmentmodalities been appropriately addressed. Thus,this review presents a description of the mostfrequent differential diagnoses and etiologiesof complete AV block in young or middle-aged asymptomatic adults and describes theirimpact on subsequent therapeutic measures. Inaddition,theauthorssuggestapotentialdiagnosticalgorithm for this group of patients. C  2012, The Authors. Journal compilation  C  2012 Wiley Periodicals, Inc. PACE, Vol. 00  2012 1  BARRA, ET AL. It is beyond the scope of this review todescribe or summarize acute iatrogenic formsof complete heart block resulting from isolatedsingle-agent drug overdose or combined co-administration of AV nodal blocking agents,AV block associated with aortic valve surgery,septal alcohol ablation, percutaneous coronaryinterventions, or electrophysiology ablation of theslow or fast pathway of the AVN. Also, as wefocus mainly on otherwise healthy asymptomaticyoungormiddle-agedadults,noreferenceswillbemade to complete AV block associated with acutecardiovascular conditions such as myocardialinfarction (MI) or cardiogenic shock. Congenitalheart block will not be thoroughly revised, asmost cases present in infancy or early childhood.The etiologies presented in this review arecompatible with advanced AV nodal conductionabnormalities as form of presentation. Differential Diagnoses Third-degree AV block can be either con-genital or acquired. Table I lists the mostcommon potential causes of acquired advancedAV block in otherwise healthy young or middle-aged adult patients, whereas Table II lists rareretiologies.In most of these conditions, atrioventricularconduction abnormalities are occasionally thefirst sign of the disease. Patients may present at Table I. Most Common Causes of Advanced AtrioventricularBlock in Otherwise Healthy Young or Middle-AgedIndividualsCoronary artery diseaseDegenerative diseases: Lenegre (sclerodegenerativeprocess involving the conduction system only) and Levdiseases (calcification of the conduction system andvalves), mitochondrial myopathyNonischemic cardiomyopathies –  De novo   or familialdilated cardiomyopathyInfectious causes – Lyme borreliosis,  Trypanosoma cruzi  infection, rheumatic fever, myocarditis, Chagasdisease,  Aspergillus   myocarditis, varicella-zoster virusinfectionRheumatic and autoimmune diseases – Giant-cellmyocarditis, ankylosing spondylitis, rheumatoidarthritis, systemic sclerosis, systemic lupuserythematosusInfiltrative processes – Amyloidosis, sarcoidosis, tumors,Non-Hodgkin lymphoma, multiple myelomaVagally inducedIatrogenic causes (including drugs) Table II. Very Rare Causes of Advanced Atrioventricular Block inOtherwise Healthy Young or Middle-Aged IndividualsNeuromuscular or neurologic disorders – Beckermuscular dystrophy, myotonic muscular dystrophy,scapuloperoneal dystrophy, oculocraniosomaticsyndromeMetabolic causes – Hypoxia, hyperkalemia, thyroiddisordersPhase IV idiopathic blockRadiation-inducedPsychiatric conditionsUnexplained apoptosis of the cardiac conduction systemAcute rheumatic feverLeft ventricular noncompactionThyroid disorders the Cardiology outpatient clinic with a baselineelectrocardiogram (ECG) or a 24-hour Holterrevealing periods of advanced atrioventricular blockdespitetheabsenceofsignificantsymptoma-tology. Often, patients are submitted to pacemakerimplantation with no further investigation, whichcomprehensively delays an objective diagnosisand appropriate therapy for the baseline condi-tion.For simplification purposes, each major eti-ologic group will be addressed in its respectivetopic. Coronary Artery Disease Acute heart block is an uncommon butserious complication of MI. Chronic heart blockassociated with Stokes-Adams attacks has beenoften assumed to be ischemic in srcin as well,andfactorssupportingitsimportancewerethenotuncommon precipitation of acute heart block bymyocardial infarction or acute ischemia and elec-trocardiographic evidence of changing T wavesin patients carrying pacemakers which would not be recognized as simply occurring secondary topacing. Nevertheless, some studies have stressedthe high incidence of primary heart block inpatients with coronary artery disease (CAD). Theincidence of CAD as a cause of chronic heart blockin the elderly was studied at necropsy by Davieset al. This author found that only 15% of studiedpatients had CAD of sufficient severity to accountfor the heart block (destruction of both bundle branches in areas of old infarctions). 4 Bundle- branch fibrosis of unknown etiology, withoutmajor damage to the contractile myocardium,was the most common cause, which explainedthe relatively normal expectation of life oncepaced. 5 The CARISMA study was the first one to2 2012  PACE, Vol. 00  ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS report on long-term cardiac arrhythmias recorded by an implantable loop recorder in patientswith left ventricular ejection fraction  ≤ 40% aftermyocardial infarction. A 10% incidence of high-degree AV block ( ≤ 30 beats per minute lasting ≥ 8 seconds) was reported during a 1.9  ±  0.5 yearfollow-up. 6 Subsequent studies have focused on therelatively poor prognosis of middle-aged patientspaced for chronic AV block when age-linkedexpectation of life was taken into account,suggesting this could result from underlying CADeven in the absence of symptoms suggesting thisdiagnosis. Ginks et al. examined a consecutiveseries of 30 patients aged 45–65 with chronicAV disease who had been referred for pacing.Coronary arteriography disclosed the presenceof severe coronary artery disease in 13 patients(43.3%) and a close relation between the levelof heart block and the distribution of the CAD(right coronary artery lesions would cause nodalischemia and conduction delay proximal to the bundle of His, while left anterior descendingocclusion would cause bundle branch ischemiaand delayed conduction distal to the bundle of His). 7 Subsequent studies have demonstrated therelationship between atrioventricular conductionabnormalities and CAD. Brueck et al. suggestedpatients with severe AV conduction disturbancesor sinus node dysfunction requiring permanentpacemaker implantation were more likely tohave CAD with subsequent need for myocardialrevascularization in the presence of at least oneatherosclerotic risk factor. 8 Tandogan et al. haveshown that the presence of first perforator andright coronary artery (RCA) lesions with poorquality of flow shown angiographically should be considered major risk factors for the need of permanent pacemaker implantation in patientswith CAD. 9 A study by Elizari et al. concludedthat one of the most common causes of hemiblockis CAD, and that the presence of left posteriorhemiblock, especially when associated with right bundle branch block, predicts a great propensitytodevelopcompleteAVblock,evenintheabsenceof symptoms. 10 Finzi et al. demonstrated thatnuclear myocardial perfusion imaging providednoninvasive evidence that transient ischemia inthe territory of the posteroseptal segment of the RCA may result in paroxysmal AV blockin patients with chronic infranodal conductionabnormalities, regardless of the symptomaticstatus. 11 Advanced degrees of AV block are aninfrequent complication of Prinzmetal’s angina. Astudy performed by Kerin et al. suggested that thetype and occurrence of a specific arrhythmia didnot help predict the presence of CAD in patientswith variant angina. Furthermore, although theauthors reported a low incidence of advancedAV block (3/26 – 11.5%), those with ST segmentelevation limited to the diaphragmatic leads(implicating the right coronary artery) were appar-ently at increased risk of high-degree AV block. 12 Nevertheless, advanced conduction abnormalitiesare not usually the form of presentation of variantangina.Despite these considerations, most studieshave shown that myocardial revascularizationdoes not result in any sustained improvementin AV conduction. Patients who have severeconduction disturbances and significant CAD maywell receive a pacemaker before revascularizationprocedures 13 , 14 [this does not apply to acutecoronary syndromes].Following pacemaker implantation, the di-agnosis of CAD through exercise stress testingmay not be possible. Studies have shown thatdobutamine stress echocardiography reduces con-siderably the level of false-positive results inthese patients and still retain sensitivity for CADequal to that of exercise thallium-201 myocardialcomputed tomography. 15 In conclusion, a clear association betweenCAD and AV nodal conduction abnormalities has been unequivocally demonstrated, in spite of theabsenceofsustainedAVconductionimprovementfollowingmyocardialrevascularization.Neverthe-less, exclusion of CAD is mandatory in patientswith cardiovascular risk factors presenting withspontaneous or exercise testing-induced completeheart block. In case a pacemaker has been alreadyimplanted,dobutaminestressechocardiographyisstrongly supported by current literature. 15 Degenerative Diseases Degenerative abnormalities in the AV nodeare the most frequent etiology of complete heart block in elderly patients. Fibrosis and sclerosisof the conduction system accounts for about one-half of cases of AV block and may be induced by several different conditions which oftencannotbeclinicallydistinguished. 16 However,theprevalence/incidence of complete degenerativeAV block in young or middle-aged individuals isunknown. Bilateral bundle branch scleroatrophyand degeneration (particularly of the middle anddistalportions)andupperinterventricularseptumcrestfibrosisaretypicalhistopathologicalfindingsof the Lenegre disease, 17 an idiopathic, fibrotic,degenerative disease restricted to the His-Purkinjesystem and not associated with inflammatory orischemic involvement of adjacent myocardium.Lenegre’s disease has not been the target of significant investigation in the last decades and PACE,Vol.00  2012 3  BARRA, ET AL. case reports of Lenegre’s disease in youth have been scarce. 18 Histological studies have shownthat diffuse fibrotic degeneration of the wholeintraventricular cardiac conduction system exists(differentiating this condition from the typicalchannelopathies), which leads to AV blockwithoutinvolvementofthesinusnodeandcardiacfibrousskeleton.SomeauthorshavesuggestedthathereditaryLenegrediseaseiscausedbyamutationin the SCN5A gene, which in combination withagingleadstoprogressivealterationinconductionvelocity. 19 In fact, the SCN5A gene encoding thehuman cardiac sodium channel alpha subunitplays a key role in cardiac electrophysiology.Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Bru-gada syndrome, and isolated progressive cardiacconduction defect (Lenegre disease). Kyndt etal. identified a G-to-T mutation at position 4372 by direct sequencing, which was predicted tochangeaglycineforanarginine(G1406R)betweenthe DIII-S5 and DIII-S6 domain of the sodiumchannel protein. This same mutation could leadeither to Brugada syndrome or to an isolatedcardiac conduction defect. 20 The most commonphenotypeofgenecarriersofaBrugadasyndrome-type SCN5A mutation is progressive cardiacconduction defects similar to the Lenegre diseasephenotype, 21 which led some authors to suggestthe existence of an overlap syndrome betweenthese two syndromes 22 and to recommend carriersof a SCN5A mutation to be followed clinicallyand electrocardiographically because of the riskassociated with severe conduction defects. 21 Lev disease is manifested by bradycardia andvarying degrees of AV block due to noninheritedprogressive degeneration and calcification of thecardiac conduction system and fibrous skeletonof the heart (mitral annulus, central fibrous body,membranousseptum,baseoftheaorta,andcrestof the ventricular septum). Lev disease has an onsetabout the fourth or fifth decade (later than Lenegredisease), although significant symptomatology isonly seen later in life. Also, contrary to Lenegredisease, it tends to affect the proximal bundle branches. 23 , 24 Mitochondrial myopathy such as Kearns-Sayre syndrome (one of the more severe andsystemically involved variants) may present asadvanced AV or intra/interventricular block,especially the former, although patients usuallyshowaplethoraofsignslikeptosis,progressiveex-ternal ophthalmoplegia, pigmentary retinopathy,cerebellar ataxia, proximal muscle weakness, anddeafness before the occurrence of complete heart block. Nevertheless, distal conduction defects areconstant findings and are a dominant factor in theprognosis of this condition. 25 , 26 The presence of advanced atrioventricularorintra/interventricularconductionabnormalitiesin a relatively young adult without structuralcardiac disease or history of myocarditis and withlow risk for coronary artery disease should raisethe suspicion for primary degenerative cardiacconduction system disease, especially if thisphenotypeissharedwithotherfamilymembersorincaseoffamilyhistoryofsuddencardiacdeathorBrugada syndrome. If a mitochondrial myopathyis suspected, the patient should be examined by aneuro-ophthalmologist.Usually, pacemaker implantation becomesnecessary during the course of both Lenegre andLev disease. Nonischemic Cardiomyopathies AV and inter/intraventricular conductionabnormalities are common findings in patientswith dilated cardiomyopathy (DCM). Inheritedmutationscauseapproximately35percentofcasesof DCM and the most frequent DCM-associatedmutations have been reported in the lamin A/Cgene(LMAC). 27 CardiacdiseaseofLMAC-mutatedpatients is classically defined by conductionsystem and rhythm disturbances occurring earlyin the course of the disease (requiring earlypacemaker implantation), followed by dilatedcardiomyopathy and heart failure. In fact, theLMAC gene mutations account for 33% of casesof DCM with AV block, all familial autosomaldominant. 28 Van Tintelen et al. highlightedthe role of LMAC mutations in patients withDCM and/or conduction disease referred to theircardiogenetics outpatient clinic, encountering asevere phenotype in p.N195K mutation carriersand preferential cardiac conduction disease inp.R225X carriers. 29 Considering DCM patients with LMAC mu-tations have a poor prognosis compared withother DCM patients, 30 genetic testing should be considered in patients with DCM whenclinical predictors of LMAC mutations arepresent (presence of skeletal muscle involvement,supraventricular arrhythmia, conduction defects,and mildly dilated ventricles were predictors of LMNA mutations in a study by Taylor et al. 30 ),regardless of family history. Also, because of highclinical variability, LMAC mutation screeningshouldbeconsideredinpatientswithfamilialloneconduction disease. 31 MutationsintheLMACgenecouldalsomimicarrhythmogenic right ventricular cardiomyopathy(ARVC) and some authors suggest LMAC geneshould be added to desmosomal genes whengenetically testing patients with suspected ARVC,particularly when there is ECG evidence forconduction disease. 32 4 2012  PACE, Vol. 00  ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS Infectious Causes High-degree heart block is an uncommon butnonnegligible manifestation of acute myocarditisin adults and may be the first manifestationof the condition. Of the 3055 adult patientswith suspected acute or chronic myocarditis whowere screened in the European Study of theEpidemiology and Treatment of InflammatoryHeart Disease, 18% had high-grade arrhythmiasincluding ventricular arrhythmias or completeheart block. 33 In a different study, the rateof advanced symptomatic heart block requiringpacemaker implantation in biopsy-proven acutelymphocytic myocarditis has been reported in upto 8.3% of cases. 34 A higher prevalence can beobserved in giant cell myocarditis, an uncommonand idiopathic disorder in which up to 25% of patients require pacemaker due to symptomaticsecond-orthird-degreeheartblock. 35 Uemaraetalstudied 50 patients with second- or third-degreeAV block (in whom the cause was not clear)through endomyocardial biopsy (EMB) performedfrom the right ventricle and concluded a highnumber of lymphocytes per 400-fold magnifiedfield was a common finding and myocardiallesions compatible with myocarditis could befound in 6% of patients. 36 Batra et al identifieda total of 40 patients younger than 20 years of agewithbiopsy-provenmyocarditisandadvancedAV block, reporting the return of AV conductionwithin 7 days in 27 patients (67%) and the needof permanent pacing in 11 patients (28%) withpersistent AV block. 37 Besides viruses, multiple agents have beenassociated with infectious myocarditis with ad-vanced AV conduction abnormalities, includ-ing protozoa, 38 rickettsia, 39 and bacteria. Twoagents deserve special emphasis: Borrelia species bacteria (Lyme disease) and  Trypanosoma cruzi  (Chagas disease). The former is the most commontick-borne disease in the Northern Hemispherecaused by at least three species of bacteria belonging to genus Borrelia:  Borrelia burgdorferi  in the United States and  Borrelia afzelii   and Borrelia garinii   in Europe.  Borrelia  is transmittedtohumansbythebiteofinfectedticksbelongingtoa few species of the genus  Ixodes.  Cardiovascularmanifestations of Lyme disease often occur within21 days of exposure and include fluctuatingdegrees of AV block even in the absence of significant symptomatology. This disease rarelyrequires permanent cardiac pacing, as it is usuallyself-limiting when treated appropriately with an-tibiotics, 40  butsomereportshaveshownthatLymecarditis can cause long-standing or irreversibleAV conduction defects despite adequate and earlyantimicrobial therapy. 41 Patients in an endemicarea presenting with cardiac symptoms shouldhave a screening electrocardiogram along withLyme titers.Chagas disease is a chronic parasitosis caused by  Trypanosoma cruzi   infection affecting mostLatin American countries and presenting as alate-developing chronic myocarditis or, much lessfrequently, an early acute myocarditis. It is themain cause of bundle branch block and AV block in endemic areas and the leading cause of cardiovascular death, mostly as a consequence of heart failure and sudden death (due to malignantventricular arrhythmias or complete heart block)in areas where the disease is endemic. 42 Although EMB has long been the gold stan-dard for confirming the diagnosis of myocarditis,preliminary studies have shown that cardiacmagnetic resonance imaging (MRI) has becomean important tool for noninvasive assessmentof patients with suspected acute or chronicmyocarditis. 43 , 44 Cardiac MRI can evaluate threemarkers of tissue injury, namely intracellularand interstitial edema, hyperemia and capillaryleakage, necrosis, and fibrosis. Furthermore, arecent consensus statement recommends thatEMB be reserved for patients who are likely tohave specific myocardial disorders with uniqueprognoses and specific treatment recommenda-tions, 45 such as cardiac sarcoidosis and giant cellmyocarditis.In conclusion, acute and chronic myocarditisare among the most important causes of advancedAV block in young and middle-aged patients,irrespective of previous symptomatology. Acutemyocarditis has been shown to be the cause of sudden death, either by malignant ventriculararrhythmias or complete heart block, in up to12% of cases in autopsy studies of patientsless than 40 years of age, military recruits,and young athletes. 46 As this condition maypresent as advanced AV block without previoussymptomatology, cardiologists should be awareof this potential diagnosis in otherwise healthyyoungormiddle-agedadultsatlowcoronaryrisk. Rheumatic or Autoimmune Diseases Several rheumatic or autoimmune diseaseshave been associated to advanced AV conductionabnormalities. In most conditions, the occurrenceof AV block is preceded by a multitude of signs orsymptoms, but, in some circumstances, completeheart block may be the first manifestation of thedisease.Giant-cell myocarditis (GCM) is a rare butdevastating disease (rate of death or transplan-tation approximately 70% at 1 year followingdiagnosis) that usually affects young, otherwisehealthy individuals and often associates withthymoma, inflammatory bowel disease, and a PACE,Vol.00  2012 5
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